Tyrosine kinase inhibitors (TKIs) have become the drugs of choice for treating a variety of human cancers (A. Arora and E. M. Scholar, J. Pharmacol. Experimtl. Therapeutics, 2005, 315, 971-979; A. Opar, Nature Rev. Drug Discovery, 2012, 11, 819-820). These drugs were developed in the late 1990s from the initial finding that 2-phenylaminopyrimidine derivatives could inhibit the action of proteins driving cell proliferation and resisting apoptosis (programmed cell death) by blocking the active site for phosphorylation of tyrosine by ATP (adenosine triphosphate) (P. Yaish, A. Gazit, C. Gilon, A. Levitzki. Science 1988, 242, 933-935; B. J. Drucker, Blood, 2008, 112, 4808-4817).
The pharmaceutical industry has produced an array of such derivatives for clinical use, for example, imatinib, nilotinib, bafetinib, erlotinib, lapatinib, and dasatinib, which display specific binding characteristics for different kinases. Derivatives bearing the 2-phenylaminopyrimidine motif are not the only examples of tyrosine kinase inhibitors (TKIs) that have activity in treating human cancers. Derivatives of indole, quinoline, and pyridine have also been developed as TKIs, for example, motesanib, sunitinib, carbozantinib, gefitinib, and vatalanib. Natural products such as emodin (an anthraquinone), geneistein (an isoflavone), radiciol (an epoxyresorcinol) also display inhibitory activity against tyrosine kinases.
Kinases driving proliferation in normal and cancer cells fall into two categories: receptor and non-receptor tyrosine kinases. Receptor kinases are the transmembrane proteins serving as receptors for growth factors that normal cells utilize to respond to environmental cues. Non-receptor kinases are essentially involved in proliferation and apoptosis resistance. Cancer cells can therefore grow without depending on extracellular factors. No external stimulation is required for carrying out phosphorylation of tyrosine by ATP. In practice, the proliferation of cancer cells can be selectively blocked by a variety of TKIs (D. S Krause and R. A. Van Etten, N. Eng. J. Med. 2005, 353, 172-187). How this happens is not precisely known. Examples include epidermal growth factor receptors (EGFR), platelet derived growth factors (PDGF), bcr-abl, c-KIT kinases, FLT kinases, platelet derived growth factors (PDGFR), vascular endothelial growth factors (VEGFR) and Src-family non-receptor kinases.
To be clinically useful, a tyrosine kinase inhibitor needs to be administered at micromolar concentrations (0.1 to 1.0 μM). However, only a few tyrosine kinase inhibitors are effective at such low concentrations.
There is a clear clinical need to improve the activity of weak tyrosine kinase inhibitors so that they can be administered to patients in micromolar, clinically useful doses, thus enabling them to be developed as potentially useful cancer medications.